The objective of the proposed research is to determine in zebrafish the molecular mechanisms that underlie the specification of the first neurons, those of the early-escape reflex. Primary motor and sensory neurons have similar genetic programs that are executed in response to different dorsal- ventral signaling. I propose to elucidate how these programs are signaled and how they determine cell specification. I will test the role that the c-ret receptor plays in local signaling by examining the expression pattern during development. I will determine if the differentiation of primary neurons requires expression of c-ret, and if c-ret is sufficient to drive differentiation of primary motor and sensory neurons. I will also ascertain the expression pattern of the putative c-ret ligand, GDNF, to see whether it is required for maintenance of primary sensory and motor neurons. Programmed cell death of some sensory neurons is coincident with decreasing levels of thyroid hormone. I will test if the specification and maintenance of other primary neurons is also dependent on alterations in long-range thyroid hormone signaling. Finally, I will examine the expression pattern of thyroid hormone receptors and their dimerization partners, the retinoid X receptors. Perturbation of the signaling with receptor antagonists should reveal the requirement for hormone action in the specification or maintenance of zebrafish primary neurons.